Composition and method for treating allergic diseases

ABSTRACT

The present invention is directed towards a pharmaceutical composition useful for the treatment of allergic rhinitis, asthma and related disorders. In one embodiment, the composition comprises, in combination, a therapeutically effective amount of at least one neurokinin antagonist, and a therapeutically effective amount of at least one 5-lipoxygenase inhibitor.

FIELD OF THE INVENTION

[0001] The present invention generally relates to compositions andmethods for treating allergic rhinitis and other respiratory diseases.It specifically discloses compositions which comprise (i) combinationsof antagonists of neurokinin receptors and antagonists of leukotrienereceptors, and (ii) combinations of antagonists of neurokinin receptorsand inhibitors of 5-lipoxygenase, as well as methods for treating theabove-noted diseases using such compositions.

BACKGROUND OF THE INVENTION

[0002] Neurokinin (“NK”) receptors such as the NK, and the NK₂ receptorsare found in the central nervous system and the circulatory system andthe peripheral tissues of mammals, and are involved in a variety ofbiological processes. Antagonists of the neurokinin receptors are,therefore, expected to be useful in the treatment or prevention ofvarious mammalian diseases such as, for example, pulmonary disorderssuch as asthma, cough, bronchospasm, chronic obstructive pulmonarydiseases, and airway hyperactivity; skin disorders and itch, forexample, atopic dermatitis, and cutaneous wheal and flare; neurogenicinflammatory diseases such as, arthritis, migraine, nociception; CNSdiseases such as anxiety, emesis, Parkinson's disease, movementdisorders and psychosis; convulsive disorders, renal disorders, urinaryincontinence, ocular inflammation, inflammatory pain, and eatingdisorders such as food intake inhibition; allergic rhinitis,neurodegenerative disorders, psoriasis, Huntington's disease, depressionand various disorders such as Crohn's disease. NK₁ receptors have beenreported to be involved in microvascular leakage and mucus secretion,and NK₂ receptors have been associated with smooth muscle contraction,making NK₁ and NK₂ receptor antagonists especially useful in thetreatment and prevention of asthma. NK₁ and NK₂ receptor antagonistshave been reported such as, for example, in U.S. Pat. Nos. 5,798,359;5,795,894; 5,789,422; 5,783,579; 5,719,156; 5,696,267; 5,691,362;5,688,960; 5,654,316 (all assigned to Schering-Plough Corporation,Madison, N.J.); and in “Recent Advances in Neurokinin ReceptorAntagonists”, by C. J. Ohnmacht Jr., et al, Annual Reports in MedicinalChemistry, A. M. Doherty Ed., 33, 71-80 (1998).

[0003] The products of the 5-lipoxygenase (“5-LO”) pathway ofarachidonic acid metabolism, particularly the leukotrienes, can mediatebronchoconstriction, mucous secretion, airway mucosal edema, chemotaxisand mobilization of cells into the airway in the inflammatory process ofasthma. Therefore, inhibition of 5-LO should help cure, reduce orprevent such diseases. Similarly, leukotriene (“LK”) antagonists play arole in treating the multitude of symptoms associated with diseases ofthe respiratory tract, such as season allergic rhinitis, perennialallergic rhinitis, common colds, sinusitis and concomitant symptomsassociated with allergic asthma. The symptoms of such diseases mayinclude sneezing, itching runny nose, nasal congestion, redness of theeye, tearing, itching of the ears or palate, and coughs associated withpostnasal drip. A discussion of leukotriene receptors may be found in R.Robertson, Prostaglandins, 31, 395 (1986), and a discussion ofleukotriene antagonists can be found in J. Musser et al, Agents andActions, 18, 332 (1986), J. Piwinski et al, Annual Reports in MedicinalChemistry, 22, 73-76 (1987), and R. Bell et al, Annual Reports inMedicinal Chemistry, 32, 91 (1997).

[0004] It would be highly desirable to enhance the efficacy of theneurokinin antagonists to improve their overall efficacy, as well as toreduce or prevent the above-noted ailments by interfering with theactivity of 5-LO and leukotriene receptors.

SUMMARY OF THE INVENTION

[0005] The afore-mentioned objective and other objectives and desiresare addressed by the present invention which, in one embodiment,provides a composition for treating and preventing allergic rhinitis andother respiratory diseases such asthma, cough, wheezing and the like.The inventive composition comprises, in combination, a therapeuticallyeffective amount of at least one neurokinin antagonist and atherapeutically effective amount of at least one leukotriene antagonist.One or more of the antagonists may be substituted by a pharmaceuticallyacceptable derivative such as salt, ester, and the like. Optionally, thecomposition may additionally contain a pharmaceutically acceptablecarrier, a decongestant (such as, for example, pseudoephedrine), a coughsuppressant (such as, for example, dexrtomethorphan), expectorant (suchas, for example, guaifenesin), analgesics (such as, for example,aspirin, ibuprofen and acetaminophen) or mixtures thereof.

[0006] Generally, the amount of the neurokinin antagonist content in theinventive composition per unit dosage form is about 1-1,000 milligramsand that of the leukotriene antagonist is about 2-500 milligrams.Preferably, the respective amounts are about 10-500 milligrams and about5-500 milligrams, and typically the respective amounts are about 50-200milligrams and 10-50 milligrams.

[0007] The present invention additionally provides a composition fortreating and preventing allergic rhinitis and other respiratory diseasessuch asthma, cough, wheezing and the like, the composition comprising,in combination, a therapeutically effective amount of at least oneneurokinin antagonist and a therapeutically effective amount of at leastone 5-LO inhibitor. One or more of the compounds may be substituted by apharmaceutically acceptable derivative such as salt, ester, and thelike. Additionally, the composition may contain a pharmaceuticallyacceptable carrier, a decongestant, a cough suppressant, andexpectorant, or mixtures thereof.

[0008] The invention further provides methods for treating asthma,chronic obstructive pulmonary disease (“COPD”), and allergic disorders,sneezing, itching runny nose, nasal congestion, redness of the eye,tearing, itching of the ears or palate, sinusitis, and coughs associatedwith postnasal drip symptoms in a mammalian organism in need of suchtreatment comprising administering the pharmaceutical compositionsdescribed above.

DETAILED DESCRIPTION OF THE INVENTION

[0009] In one embodiment, the present invention discloses pharmaceuticalcompositions that are useful in treating and preventing allergicrhinitis, asthma and related disorders. The composition comprises, incombination, a therapeutically effective amount of at least oneneurokinin antagonist and a therapeutically effective amount of at leastone leukotriene antagonist. One or more of the antagonists may besubstituted by a pharmaceutically acceptable derivative such as salt,ester, and the like.

[0010] Several neurokinin antagonists that are known currently areuseful in the practice of the present invention. Non-limiting examplesof such useful neurokinin antagonists include, for example, thosebelonging to the chemical class of oximes, hydrazones, piperidines,piperazines, aryl alkyl amines, hydrazones, nitroalkanes, amides,isoxazolines, quinolines, isoquinolines, azanorbornanes, naphthyridines,benzodiazepines and the like. Many are disclosed in the U.S. patentscited earlier in this patent application. Preferred NK antagonists arethose disclosed in the above-noted U.S. Pat. Nos. 5,798,359; 5,795,894;5,789,422; 5,783,579; 5,719,156; 5,696,267; 5,691,362; 5,688,960;5,654,316. The general formula of some of so-disclosed compounds is:

[0011] wherein Z is

[0012] where B is OR₂; NR₆COR₂, CONR₆R₇ or NR₂CONR₆R₇,

[0013] m=0 or 1,

[0014] P is R₅-aryl; or R₅-heteroaryl; and

[0015] Y is H, CR₂R₃CO₂R₆; CR₂R₃CONR₆R₇ or CR₂R₃NR₆COR₂;

[0016] a=b=0, 1 or 2;

[0017] Q has the same definitions as P above, with the proviso that Pand Q may be the same or different;

[0018] A is ═N—OR₁; ═N—NR₂R₃; or ═CR₁R₂;

[0019] X is —O—; —NR₆—; —N(R₆)CO—; or —CO—NR₆—;

[0020] T is R₄-aryl; R₄-heteroaryl; R₄-cycloalkyl; or R₂-bridgedcycloalkyl;

[0021] R₁ is H, C₁-C₆ alkyl; or (CH₂)_(n)—G where n=1-6;

[0022] G is H; R₄-aryl; R₄-heteroaryl; COR₆; CO₂R₆; CONR₆R₇; CN; OCOR₆;SO₃R₂;

[0023] C(═NOR₂)NR₆R₇; C(═NR₂)NR₆R₇, with the proviso that when n≠1, Gcan additionally be OR₆, NR₆R₇ or NR₆(CO)R₇;

[0024] R₂ and R₃ are independently H or C₁-C₆ alkyl;

[0025] R₄ and R₅ are independently 1, 2 or 3 substituents independentlyselected from OR₂, OC(O)R₂, OC(O)NR₆R₇, C₁-C₆ alkyl, H, halogen, CF₃,C₂F₅, or OCF₃; and

[0026] R₆ and R₇ are independently selected from H or C₁-C₆ alkyl, withthe proviso that when R₆ and R₇ are part of NR₆R₇ then said NR₆R₇ mayform part of a C₅-C₆ ring wherein 0-2 ring members are selected from thegroup consisting of —O—, —S— and —NR₂—, with the further proviso thatsaid C₅-C₆ ring may contain substituents on said ring with saidsubstituents being selected from the group consisting of hydrogen,halogen, —OR₆ and —COOR₆.

[0027] Particularly preferred neurokinin antagonists are those disclosedin the above-mentioned U.S. patents, and belonging to the generalformula:

[0028] and stereoisomers thereof. More particularly preferred are thestereoisomers with the general formula:

[0029] where R is H; CH₂CONH₂; CH₂CONHMe; CH₂CONMe₂ or

[0030] Illustrative non-limiting examples of leukotriene antagonistsuseful in the practice of the present invention include montelukast(from Merck & Company), pranlukast (from Ono Pharmaceutical CompanyLimited, CAS Registry Number: 103177-37-3), zafirlukast (from ZenecaPharmaceuticals; CAS Registry Number: 107753-78-6), CP-195494 (fromPfizer, Incorporated), and the like. The technical name of montelukastis[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneaceticacid. The technical name of pranlukast isN-[4-oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-8-yl]-4-(4-phenylbutoxy)-benzamide.The technical name of zafirlukast is[3-[[2-methoxy-4-[[[2-methylphenyl)sulfonyl]amino]carbonyl]phenyl]methyl]-1-methyl-1H-indol-5-yl]-carbamicacid, cyclopentylester, disclosed in EP-00199543. A particularly usefulleukotriene is montelukast. Montelukast is a leukotriene D4 antagonistcapable of antagonizing the receptors for the cysteinyl leukotrienes.This compound is described in EP 480,717. A preferred pharmaceuticallyacceptable salt of montelukast is the monosodium salt, also known asmontelukast sodium (CAS Registry Number: 151767-02-1).

[0031] In another embodiment, this invention discloses otherpharmaceutical compositions that are useful in treating and preventingallergic rhinitis, asthma and related disorders. The compositioncomprises, in combination, a therapeutically effective amount of atleast one neurokinin antagonist and a therapeutically effective amountof at least one inhibitor of 5-lipoxygenase. One or more of thecompounds may be substituted by a pharmaceutically acceptable derivativesuch as salt, ester, and the like.

[0032] Non-limiting examples of useful neurokinin antagonists are thosethat are disclosed in the above-cited U.S. patents, including, forexample, the compounds where R is H; CH₂CONH₂; CH₂CONHMe; CH₂CONMe₂ or

[0033] Useful 5-LO inhibitors include, for example, Zileuton (fromAbbott Laboratories, CAS Registry Number: 111406-87-2) and Atreluton(from Abbott Laboratories, CAS Registry Number: 154355-76-7). Thetechnical name of Zileuton isN-(1-benzo[b]thien-2-ylethyl)-N-hydroxy-urea. The technical name ofAtreluton isN-[(1R)-3-[5-[(4-fluorophenyl)methyl]-2-thienyl]-1-methyl-2-propynyl]-N-hydroxyurea.

[0034] In yet another embodiment, this invention discloses a method forthe treatment of asthma, allergic rhinitis, and other allergicdisorders, sneezing, itching runny nose, nasal congestion, redness ofthe eye, tearing, itching of the ears or palate, wheezing, sinusitis,and coughs associated with postnasal drip symptoms in a mammalianorganism in need of such treatment comprising administering apharmaceutical composition which comprises the neurokinin antagonist andthe leukotriene antagonist as described above.

[0035] In a further embodiment, the present invention teaches a methodfor the treatment of asthma, allergic rhinitis, and other allergicdisorders, sneezing, itching runny nose, nasal congestion, redness ofthe eye, tearing, itching of the ears or palate, wheezing, sinusitis,and coughs associated with postnasal drip symptoms in a mammalianorganism in need of such treatment comprising administering apharmaceutical composition which comprises the neurokinin antagonist andthe 5-LO inhibitor as described above.

[0036] In the pharmaceutical compositions and methods of the presentinvention, the active ingredients will typically be administered inadmixture with suitable pharmaceutical diluents, excipients or carriers(collectively referred to herein as carrier materials) suitably selectedwith respect to the intended form of administration, i.e. oral tablets,capsules (either solid-filled, semi-solid filled or liquid filled),powders for constitution, oral gels, elixirs, dispersible granules,syrups, suspensions, and the like, and consistent with conventionalpharmaceutical practices. For example, for oral administration in theform of tablets or capsules, the active drug component may be combinedwith any oral non-toxic pharmaceutically acceptable inert carrier, suchas lactose, starch, sucrose, cellulose, magnesium stearate, dicalciumphosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms)and the like. Moreover, when desired or needed, suitable binders,lubricants, disintegrating agents and coloring agents may also beincorporated in the mixture. Powders and tablets may be comprised offrom about 5 to about 95 percent inventive composition. Suitable bindersinclude starch, gelatin, natural sugars, corn sweeteners, natural andsynthetic gums such as acacia, sodium alginate, carboxymethylcellulose,polyethylene glycol and waxes. Among the lubricants there may bementioned for use in these dosage forms, boric acid, sodium benzoate,sodium acetate, sodium chloride, and the like. Disintegrants includestarch, methylcellulose, guar gum and the like. Sweetening and flavoringagents and preservatives may also be included where appropriate. Some ofthe terms noted above, namely disintegrants, diluents, lubricants,binders and the like, are discussed in more detail below.

[0037] Additionally, the compositions of the present invention may beformulated in sustained release form to provide the rate controlledrelease of any one or more of the components or active ingredients tooptimize the therapeutic effects, i.e. neurokinin antagonism,leukotriene antagonism, 5-LO inhibition and the like. Suitable dosageforms for sustained release include layered tablets containing layers ofvarying disintegration rates or controlled release polymeric matricesimpregnated with the active components and shaped in tablet form orcapsules containing such impregnated or encapsulated porous polymericmatrices.

[0038] Liquid form preparations include solutions, suspensions andemulsions. As an example may be mentioned water or water-propyleneglycol solutions for parenteral injections or addition of sweeteners andopacifiers for oral solutions, suspensions and emulsions. Liquid formpreparations may also include solutions for intranasal administration.

[0039] Aerosol preparations suitable for inhalation may includesolutions and solids in powder form, which may be in combination with apharmaceutically acceptable carrier such as inert compressed gas, e.g.nitrogen.

[0040] For preparing suppositories, a low melting wax such as a mixtureof fatty acid glycerides such as cocoa butter is first melted, and theactive ingredient is dispersed homogeneously therein by stirring orsimilar mixing. The molten homogeneous mixture is then poured intoconvenient sized molds, allowed to cool and thereby solidify.

[0041] Also included solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

[0042] The compounds of the invention may also be deliverabletransdermally. The transdermal compositions may take the form of creams,lotions, aerosols and/or emulsions and can be included in a transdermalpatch of the matrix or reservoir type as a re conventional in the artfor this purpose.

[0043] Preferably the compound is administered orally.

[0044] Preferably, the pharmaceutical preparation is in a unit dosageform. In such form, the preparation is subdivided into suitably sizedunit doses containing appropriate quantities of the active components,e.g., an effective amount to achieve the desired purpose.

[0045] The quantity of the inventive active composition in a unit doseof preparation may be generally varied or adjusted from about 0.01milligrams to about 1,000 milligrams, preferably from about 0.01 toabout 750 milligrams, more preferably from about 0.01 to about 500milligrams, and typically from about 0.01 to about 250 milligrams,according to the particular application. The actual dosage employed maybe varied depending upon the patient's age, sex, weight and severity ofthe condition being treated. Such techniques are well known to thoseskilled in the art. Generally, the human oral dosage form containing theactive ingredients can be administered 1 or 2 times per day. The amountand frequency of the administration will be regulated according to thejudgment of the attending clinician. A generally recommended dailydosage regimen for oral administration may range from about 0.04milligrams to about 4,000 milligrams per day, in single or divideddoses.

[0046] Capsule—refers to a special container or enclosure made of methylcellulose, polyvinyl alcohols, or denatured gelatins or starch forholding or containing compositions comprising the active ingredients.Hard shell capsules are typically made of blends of relatively high gelstrength bone and pork skin gelatins. The capsule itself may containsmall amounts of dyes, opaquing agents, plasticizers and preservatives.

[0047] Tablet—refers to a compressed or molded solid dosage formcontaining the active ingredients with suitable diluents. The tablet canbe prepared by compression of mixtures or granulations obtained by wetgranulation, dry granulation or by compaction.

[0048] Oral gels—refers to the active ingredients dispersed orsolubilized in a hydrophillic semi-solid matrix.

[0049] Powders for constitution refers to powder blends containing theactive ingredients and suitable diluents which can be suspended in wateror juices.

[0050] Diluent—refers to substances that usually make up the majorportion of the composition or dosage form. Suitable diluents includesugars such as lactose, sucrose, mannitol and sorbitol; starches derivedfrom wheat, corn rice and potato; and celluloses such asmicrocrystalline cellulose. The amount of diluent in the composition canrange from about 10 to about 90% by weight of the total composition,preferably from about 25 to about 75%, more preferably from about 30 toabout 60% by weight, even more preferably from about 12 to about 60%.

[0051] Disintegrants—refers to materials added to the composition tohelp it break apart (disintegrate) and release the medicaments. Suitabledisintegrants include starches; “cold water soluble” modified starchessuch as sodium carboxymethyl starch; natural and synthetic gums such aslocust bean, karaya, guar, tragacanth and agar; cellulose derivativessuch as methylcellulose and sodium carboxymethylcellulose;microcrystalline celluloses and cross-linked microcrystalline cellulosessuch as sodium croscarmellose; alginates such as alginic acid and sodiumalginate; clays such as bentonites; and effervescent mixtures. Theamount of disintegrant in the composition can range from about 2 toabout 15% by weight of the composition, more preferably from about 4 toabout 10% by weight.

[0052] Binders—refers to substances that bind or “glue” powders togetherand make them cohesive by forming granules, thus serving as the“adhesive” in the formulation. Binders add cohesive strength alreadyavailable in the diluent or bulking agent. Suitable binders includesugars such as sucrose; starches derived from wheat, corn rice andpotato; natural gums such as acacia, gelatin and tragacanth; derivativesof seaweed such as alginic acid, sodium alginate and ammonium calciumalginate; cellulosic materials such as methylcellulose and sodiumcarboxymethylcellulose and hydroxypropylmethylcellulose;polyvinylpyrrolidone; and inorganics such as magnesium aluminumsilicate. The amount of binder in the composition can range from about 2to about 20% by weight of the composition, more preferably from about 3to about 10% by weight, even more preferably from about 3 to about 6% byweight.

[0053] Lubricant—refers to a substance added to the dosage form toenable the tablet, granules, etc. after it has been compressed, torelease from the mold or die by reducing friction or wear. Suitablelubricants include metallic stearates such as magnesium stearate,calcium stearate or potassium stearate; stearic acid; high melting pointwaxes; and water soluble lubricants such as sodium chloride, sodiumbenzoate, sodium acetate, sodium oleate, polyethylene glycols andd′l-leucine. Lubricants are usually added at the very last step beforecompression, since they must be present on the surfaces of the granulesand in between them and the parts of the tablet press. The amount oflubricant in the composition can range from about 0.2 to about 5% byweight of the composition, preferably from about 0.5 to about 2%, morepreferably from about 0.3 to about 1.5% by weight.

[0054] Glidents—materials that prevent caking and improve the flowcharacteristics of granulations, so that flow is smooth and uniform.Suitable glidents include silicon dioxide and talc. The amount ofglident in the composition can range from about 0.1% to about 5% byweight of the total composition, preferably from about 0.5 to about 2%by weight.

[0055] Coloring agents—excipients that provide coloration to thecomposition or the dosage form. Such excipients can include food gradedyes and food grade dyes adsorbed onto a suitable adsorbent such as clayor aluminum oxide. The amount of the coloring agent can vary from about0.1 to about 5% by weight of the composition, preferably from about 0.1to about 1%.

[0056] Bioavailability—refers to the rate and extent to which the activedrug ingredient or therapeutic moiety is absorbed into the systemiccirculation from an administered dosage form as compared to a standardor control.

[0057] Conventional methods for preparing tablets are known. Suchmethods include dry methods such as direct compression and compressionof granulation produced by compaction, or wet methods or other specialprocedures. Conventional methods for making other forms foradministration such as, for example, capsules, suppositories and thelike are also well known.

[0058] It will be apparent to those skilled in the art that manymodifications, variations and alterations to the present disclosure,both to materials and methods, may be practiced. Such modifications,variations and alterations are intended to be within the spirit andscope of the present invention.

What is claimed is:
 1. A pharmaceutical composition comprising, incombination, a therapeutically effective amount of at least oneneurokinin antagonist or a pharmaceutically acceptable derivativethereof, and a therapeutically effective amount of at least oneleukotriene antagonist or a pharmaceutically acceptable derivativethereof.
 2. The pharmaceutical composition of claim 1 , wherein saidneurokinin antagonist or its pharmaceutically acceptable derivative ispresent in amounts of 1-1,000 milligrams per unit dosage of saidpharmaceutical composition.
 3. The pharmaceutical composition of claim 1, wherein said neurokinin antagonist or its pharmaceutically acceptablederivative is present in amounts of 10-500 milligrams per unit dosage ofsaid pharmaceutical composition.
 4. The pharmaceutical composition ofclaim 1 , wherein said neurokinin antagonist or its pharmaceuticallyacceptable derivative is present in amounts of 50-200 milligrams perunit dosage of said pharmaceutical composition.
 5. The pharmaceuticalcomposition of claim 1 , wherein said leukotriene antagonist or itspharmaceutically acceptable derivative is present in amounts of 2-500milligrams per unit dosage of said pharmaceutical composition.
 6. Thepharmaceutical composition of claim 1 , wherein said leukotrieneantagonist or its pharmaceutically acceptable derivative is present inamounts of 5-100 milligrams per unit dosage of said pharmaceuticalcomposition.
 7. The pharmaceutical composition of claim 1 , wherein saidleukotriene antagonist or its pharmaceutically acceptable derivative ispresent in amounts of 10-50 milligrams per unit dosage of saidpharmaceutical composition.
 8. The pharmaceutical composition of claim 1, wherein said neurokinin antagonist is a piperidine, piperazine, oxime,hydrazone, olefin, quinoline, isoquinoline, nitroalkane, amide,isoxazoline, azanorbornane, naphthyridine, benzodiazepine, or aryl alkylamine.
 9. The pharmaceutical composition of claim 1 , wherein saidneurokinin antagonist is a compound having the general formula:

wherein Z is

where B is OR₂; NR₆COR₂, CONR₆R₇ or NR₂CONR₆R₇, m=0 or 1, P is R₅-aryl;or R₅-heteroaryl; and Y is H, CR₂R₃CO₂R₆; CR₂R₃CONR₆R₇ or CR₂R₃NR₆COR₂;a=b=0, 1 or 2; Q has the same definitions as P above, with the provisothat P and Q may be the same or different; A is ═N—OR₁; ═N—NR₂R₃; or═CR₁R₂; X is —O—; —NR₆—; —N(R₆)CO—; or —CO—NR₆—; T is R₄-aryl;R₄-heteroaryl; R₄-cycloalkyl; or R₂-bridged cycloalkyl; R₁ is H, C₁-C₆alkyl; or (CH₂)_(n)—G where n=1-6; G is H; R₄-aryl; R₄-heteroaryl; COR₆;CO₂R₆; CONR₆R₇; CN; OCOR₆; SO₃R₂; C(═NOR₂)NR₆R₇; C(═NR₂)NR₆R₇, with theproviso that when n≠1, G can additionally be OR₆, NR₆R₇ or NR₆(CO)R₇; R₂and R₃ are independently H or C₁-C₆ alkyl; R₄ and R₅ are independently1, 2 or 3 substituents independently selected from OR₂, OC(O)R₂,OC(O)NR₆R₇, C₁-C₆ alkyl, H, halogen, CF₃, C₂F₅, or OCF₃; and R₆ and R₇are independently selected from H or C₁-C₆ alkyl, with the proviso thatwhen R₆ and R₇ are part of NR₆R₇ then said NR₆R₇ may form part of aC₅-C₆ ring wherein 0-2 ring members are selected from the groupconsisting of —O—, —S— and —NR₂—, with the further proviso that saidC₅-C₆ ring may contain substituents on said ring with said substituentsbeing selected from the group consisting of hydrogen, halogen, —OR₆ and—COOR₆.
 10. The pharmaceutical composition of claim 1 , wherein saidneurokinin antagonist is a compound having the general formula:

and stereoisomers thereof, where R═H; CH₂CONH₂; CH₂CONHMe; CH₂CONMe₂ or


11. The pharmaceutical composition of claim 1 , wherein said neurokininantagonist is a compound having the general formula:

where R is H; CH₂CONH₂; CH₂CONHMe; CH₂CONMe₂ or


12. The pharmaceutical composition of claim 11 , wherein said neurokininantagonist is the compound where R is CH₂CONH₂.
 13. The pharmaceuticalcomposition of claim 11 , wherein said neurokinin antagonist is thecompound where R is CH₂CONHMe.
 14. The pharmaceutical composition ofclaim 1 , wherein said leukotriene antagonist is selected from the groupconsisting of montelukast, montelukast sodium, pranlukast, zafirlukastand CP-195494.
 15. The pharmaceutical composition of claim 14 , whereinsaid leukotriene antagonist is montelukast sodium.
 16. Thepharmaceutical composition of claim 1 , additionally containing one ormore materials selected from the group consisting of a pharmaceuticallyacceptable carrier, a decongestant, a cough suppressant and anexpectorant.
 17. A method for the treatment of asthma, allergicrhinitis, chronic obstructive pulmonary disease, sneezing, itching runnynose, nasal congestion, redness of the eye, tearing, itching of the earsor palate, wheezing, coughs associated with postnasal drip symptoms andrespiratory disorders associated with allergy in a mammalian organism inneed of such treatment, said treatment comprising: administering apharmaceutical composition comprising, in combination, a therapeuticallyeffective amount of at least one neurokinin antagonist or apharmaceutically acceptable derivative thereof and a therapeuticallyeffective amount of at least one leukotriene antagonist or apharmaceutically acceptable derivative thereof.
 18. A pharmaceuticalcomposition comprising, in combination, a therapeutically effectiveamount of at least one neurokinin antagonist or a pharmaceuticallyacceptable derivative thereof, and a therapeutically effective amount ofat least one inhibitor of 5-lipoxygenase or a pharmaceuticallyacceptable derivative thereof.
 19. The pharmaceutical composition ofclaim 18 , wherein said neurokinin antagonist is a piperidine,piperazine, oxime, hydrazone, olefin, quinoline, isoquinoline,nitroalkane, amide, isoxazoline, azanorbornane, naphthyridine,benzodiazepine, or aryl alkyl amine.
 20. The pharmaceutical compositionof claim 18 , wherein said neurokinin antagonist is a compound havingthe general formula:

wherein Z is

where B is OR₂; NR₆COR₂, CONR₆R₇ or NR₂CONR₆R₇, m=0 or 1, P is R₅-aryl;or R₅-heteroaryl; and Y is H, CR₂R₃CO₂R₆; CR₂R₃CONR₆R₇ or CR₂R₃NR₆COR₂;a=b=0, 1 or 2; Q has the same definitions as P above, with the provisothat P and Q may be the same or different; A is ═N—OR₁; ═N—NR₂R₃; or═CR₁R₂; X is —O—; —NR₆—; —N(R₆)CO—; or —CO—NR₆—; T is R₄-aryl;R₄-heteroaryl; R₄-cycloalkyl; or R₂-bridged cycloalkyl; R₁ is H, C₁-C₆alkyl; or (CH₂)_(n)—G where n=1-6; G is H; R₄-aryl; R₄-heteroaryl; COR₆;CO₂R₆; CONR₆R₇; CN; OCOR₆; SO₃R₂; C(═NOR₂)NR₆R₇; C(═NR₂)NR₆R₇, with theproviso that when n≠1, G can additionally be OR₆, NR₆R₇ or NR₆(CO)R₇; R₂and R₃ are independently H or C₁-C₆ alkyl; R₄ and R₅ are independently1, 2 or 3 substituents independently selected from OR₂, OC(O)R₂,OC(O)NR₆R₇, C₁-C₆ alkyl, H, halogen, CF₃, C₂F₅, or OCF₃; and R₆ and R₇are independently selected from H or C₁-C₆ alkyl, with the proviso thatwhen R₆ and R₇ are part of NR₆R₇ then said NR₆R₇ may form part of aC₅-C₆ ring wherein 0-2 ring members are selected from the groupconsisting of —O—, —S— and —NR₂—, with the further proviso that saidC₅-C₆ ring may contain substituents on said ring with said substituentsbeing selected from the group consisting of hydrogen, halogen, —OR₆ and—COOR₆.
 21. The pharmaceutical composition of claim 18 , wherein saidneurokinin antagonist is a compound having the general formula:

and stereoisomers thereof, where R═H; CH₂CONH₂; CH₂CONHMe; CH₂CONMe₂ or


22. The pharmaceutical composition of claim 18 , wherein said neurokininantagonist is a compound having the general formula:

where R is H; CH₂CONH₂; CH₂CONHMe; CH₂CONMe₂ or


23. The pharmaceutical composition of claim 18 , wherein said neurokininantagonist is present in amounts of about 1-1,000 milligrams per unitdosage of said composition.
 24. The pharmaceutical composition of claim18 , wherein said inhibitor of 5-lipoxygenase is present in amounts ofabout 2-500 milligrams per unit dosage of said composition.
 25. Thepharmaceutical composition of claim 18 , wherein said inhibitor of5-lipoxygenase is Zileuton or Atreluton.
 26. The pharmaceuticalcomposition of claim 25 , wherein said inhibitor of 5-lipoxygenase isZileuton.
 27. The composition of claim 18 , additionally containing oneor more materials selected from the group consisting of apharmaceutically acceptable carrier, a decongestant, a cough suppressantand an expectorant.
 28. A method for the treatment of asthma, allergicrhinitis, chronic obstructive pulmonary disease, sneezing, itching runnynose, nasal congestion, redness of the eye, tearing, itching of the earsor palate, wheezing, coughs associated with postnasal drip symptoms andrespiratory disorders associated with allergy in a mammalian organism inneed of such treatment, said treatment comprising: administering apharmaceutical composition comprising, in combination, a therapeuticallyeffective amount of at least one neurokinin antagonist or apharmaceutically acceptable derivative thereof, and a therapeuticallyeffective amount of at least one inhibitor of 5-lipoxygenase or apharmaceutically acceptable derivative thereof.
 29. The method of claim17 or claim 28 , wherein said neurokinin antagonist is a compound havingthe general formula:

wherein Z is

where B is OR₂; NR₆COR₂, CONR₆R₇ or NR₂CONR₆R₇, m=0 or 1, P is R₅-aryl;or R₅-heteroaryl; and Y is H, CR₂R₃CO₂R₆; CR₂R₃CONR₆R₇ or CR₂R₃NR₆COR₂;a=b=0, 1 or 2; Q has the same definitions as P above, with the provisothat P and Q may be the same or different; A is ═N—OR₁; ═N—NR₂R₃; or═CR₁R₂; X is —O—; —NR₆—; —N(R₆)CO—; or —CO—NR₆—; T is R₄-aryl;R₄-heteroaryl; R₄-cycloalkyl; or R₂-bridged cycloalkyl; R₁ is H, C₁-C₆alkyl; or (CH₂)_(n)—G where n=1-6; G is H; R₄-aryl; R₄-heteroaryl; COR₆;CO₂R₆; CONR₆R₇; CN; OCOR₆; SO₃R₂; C(═NOR₂)NR₆R₇; C(═NR₂)NR₆R₇, with theproviso that when n≠1, G can additionally be OR₆, NR₆R₇ or NR₆(CO)R₇; R₂and R₃ are independently H or C₁-C₆ alkyl; R₄ and R₅ are independently1, 2 or 3 substituents independently selected from OR₂, OC(O)R₂,OC(O)NR₆R₇, C₁-C₆ alkyl, H, halogen, CF₃, C₂F₅, or OCF₃; and R₆ and R₇are independently selected from H or C₁-C₆ alkyl, with the proviso thatwhen R₆ and R₇ are part of NR₆R₇ then said NR₆R₇ may form part of aC₅-C₆ ring wherein 0-2 ring members are selected from the groupconsisting of —O—, —S— and —NR₂—, with the further proviso that saidC₅-C₆ ring may contain substituents on said ring with said substituentsbeing selected from the group consisting of hydrogen, halogen, —OR₆ and—COOR₆.
 30. The method of claim 17 or claim 28 , wherein saidleukotriene antagonist is selected from the group consisting ofmontelukast, montelukast sodium, pranlukast, zafirlukast and CP-195494.31. The method of claim 17 or claim 28 , wherein said inhibitor of5-lipoxygenase is Zileuton or Atreluton.